Pharmaceutically useful meso-azacyclic amides of imidazopyridine carboxylic acids and analogs thereof

ABSTRACT

The imidazopyridines containing meso-azacycle side chains as described herein find utility as antagonists of the serotonin 5-HT 3  receptor. As such they are useful for the treatment of humans and animals wherein antagonism of 5-HT 3  receptors is benefical. Therapy is indicated for, but not limited to, the treatment of anxiety, psychoses, depression (especially depression accompanied by anxiety), cognitive disorders, substance abuse dependence and/or withdrawal, gastrointestinal motility disturbances (including esophageal reflux, dyspepsia, irritable bowel syndrome), emesis caused by chemotherapeutic agents, and visceral pain. Additionally, the compounds of the present invention may find utility as enhancers of nasal absorption of bioactive compounds.

BACKGROUND OF THE INVENTION

The invention herein is directed to compounds and a method of treatinggastrointestinal motility disorders of a mammal by administering to themammal in need thereof a therapeutically effective amount of a compounddisclosed herein or a pharmaceutically acceptable salt thereof. Themethod can be practiced to treat gastrointestinal motility disorderssuch as gastroesophageal reflux, diseases characterized by delayedgastric emptying, ileus, irritable bowel syndrome, and the like. Thecompounds of the invention are serotonergic 5-HT₃ antagonists and assuch are useful for the treatment of conditions, for example, such asanxiety, psychoses and depression.

There are classes of compounds known for the treatment of suchdisorders. For example, azatetracycle compounds are disclosed inco-pending U.S. patent application Ser. No. 07/515,391 filed Apr. 27,1990, and N-Azabicyclo [3.3.0] octane amides of aromatic acids aredisclosed in copending application Serial No. 07/406,205 filed Sep. 11,1989 now U.S. Pat. No. 4,992,461.

Aza-adamantyl compounds are disclosed in U.S. Pat. No. 4,816,453 and arementioned generically in U.K. Patent 2,152,049A and European application0189002A2.

Azabicyclic nonanes are disclosed in European Patent application0094742A2. Additional azabicyclic compounds are disclosed in U.S. Pat.Nos. 4,797,387 and 4,797,406.

Benzamides have been known as 5-HT₃ antagonists and as compoundspossessing gastrointestinal motility-enhancing properties. Benzamides ofthe following formula: ##STR1## compounds wherein X can be anazabicycloalkane moiety and which exhibit gastrointestinal motilityenhancing and/or 5-HT₃ antagonist properties are disclosed in EP0094742A2 and in U.S. Pat. No. 4,797,406. In addition, UK Patent2,152,049 discloses that certain benzamide derivatives exhibit serotoninM antagonistic activity.

Indoleamides of the following formula have also been described aspossessing gastrointestinal motility-enhancing and/or 5-HT₃ antagonistproperties: ##STR2## Compounds wherein X contains an aminergic sidechain or an azabicycloalkane moiety are described in U.S. Pat. No.4,797,406.

European patent publication number 0,230,718 discloses certainsubstituted benzamide derivatives, substituted with piperidinylanalogues as having gastrointestinal motility-enhancing and/orantiemetic activity and/or 5-HT receptor antagonist activity.

J. Heterocyclic Chemistry (1987) 24: 47 describes the preparation of thefollowing compound: No substitution is shown in the phenyl ring and noutility is described. ##STR3##

Pharmaceutical Sciences (1987) 76: 416 describes compounds of genericscope. Utility as anti-arrythmic agents is described. ##STR4## n=1 or 2R₁ =H, 2-Me, 4-NH₂, 4-OMe, 4-NHCO₂ Et, 2-OEt, 4-OEt, 3- or 4-NMe₂, 3- or4-NO₂ ; R₂ =H or 6-Me.

JP Patent 58083694 A2 and JP 0027355B describe antiarrythmic agents ofthe following formula wherein n=1 or 2; R₁ or R₂ are both Me or R₁ is Hwhile R₂ is nitro, dilower alkylamino, lower alkoxycarbonylamino, orethoxy. ##STR5##

EP Patent 39,903 and U.S. Pat. No. 4,617,401 describe compounds of thefollowing formula wherein X is NH or O and R is H, OMe, OH, or NH₂ and Zis a lone electron pair or optionally substituted alkyl group. Thecompounds are described as spasmolytic, antiarrythmic, andneuromuscular-blocking agents. ##STR6##

SUMMARY OF THE INVENTION

The compounds of examples 1-8 find utility as antagonists of theserotonin 5-HT₃ receptor. As such they are useful for the treatment ofhumans and animals wherein antagonism of 5-HT₃ receptors is beneficial.Therapy is indicated for, but not limited to, the treatment of anxiety,psychoses, depression (especially depression accompanied by anxiety),cognitive disorders, substance abuse dependence and/or withdrawal,gastrointestinal motility disturbancies (including esophageal reflux,dyspepsia, irritable bowel syndrome), emesis caused by chemotherapeuticagents, and visceral pain. Additionally, the compounds of the presentinvention may find utility as enhancers of nasal absorption of bioactivecompounds.

DETAILED DESCRIPTION OF THE INVENTION

The invention herein is directed to compounds of the formula

    Ar--CO--X--Z

the stereoisomers and pharmaceutically acceptable salts thereof whereinAr repsents a radical of the formula. ##STR7## Wherein in Group A, R₁ isH, or C₁₋₆ alkyl, R₂ is H, or halogen;

In Group B, K is N or CR₄, L is N or CR₅, R₂ and R₃ are independently Hor halogan, R₄ is H, or C₁₋₆ alkoxy, R₅ is H, halogen, CF₃, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylsulfinyl,C₁₋₇ acyl, cyano, C₁₋₆ alkoxycarbonyl, C₁₋₇ acylamino, hydroxy, nitro,amino, aminocarbonyl, or aminosulfonyl optionally N-substituted by oneor two groups selected from C₁₋₆ alkyl, C₃₋₈ cycloalkyl, and C₃₋₈cycloalkylC₁₋₄ alkyl or disubstituted by C₄ or C₅ polymethylene, phenylor phenyl C₁₋₄ alkyl group optionally substituted in the phenyl ring byone or two of halogen, C₁₋₆ alkoxy or C₁₋₆ alkyl groups;

In Group C, M is N or CR₄ R₂ and R₃ are independently H or halogen, R₄is H or C₁₋₆ alkoxy, R₅ is H, halogen, CF₃, C₁₋₆ alkyl, C₁₋₆ alkoxy,C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylsulfinyl, C₁₋₇ acyl,cyano, C₁₋₆ alkoxycarbonyl, C₁₋₇ acylamino, hydroxy, nitro, amino,aminocarbonyl, or aminosulfonyl optionally N-substituted by one or twogroups selected from C₁₋₆ alkyl, C₃₋₈ cycloalkyl, and C₃₋₈cycloalkylC₁₋₄ alkyl or disubstituted by C₄ or C₅ polymethylene, phenylor phenyl C₁₋₄ alkyl group optionally substituted in the phenyl ring byone or two of halogen, C₁₋₆ alkoxy or C₁₋₆ alkyl groups;

In Group D, one of R₆ or R₇ is C₁₋₆ alkyl and the other is C₁₋₆ alkyl,phenyl or phenyl C₁₋₄ alkyl optionally substituted in either phenyl ringby one or two of C₁₋₆ alkyl, C₁₋₆ alkoxy, or halogen, or R₆ and R₇together are C₂₋₆ polymethylene or C₂₋₅ polymethylene interrupted by an--O-- linkage, R₂ and R₃ are independently H or halogen;

In Group E, R₄ is H or C₁₋₆ alkoxy, R₅ is H or C₁₋₆ alkoxy, R₂ is H,halogen, CF₃, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₁₋₆alkylsulfonyl, C₁₋₆ alkylsulfinyl, C₁₋₇ acyl, cyano, C₁₋₆alkoxycarbonyl, C₁₋₇ acylamino, hydroxy, nitro, amino, aminocarbonyl, oraminosulfonyl, optionally N-substituted by one or two groups selectedfrom C₁₋₆ alkyl, C₃₋₈ cycloalkyl, and C₃₋₈ cycloalkylC₁₋₄ alkyl ordisubstituted by C₄ or C₅ polymethylene; phenyl or phenyl C₁₋₄ alkylgroup optionally substituted in the phenyl ring by one or two ofhalogen, C₁₋₆ alkoxy or C₁₋₆ alkyl groups, R₂ and R₃ are independently Hor halogen;

In Group F, R₁ is H or C₁₋₆ alkyl, R₂ is H or halogen; and

In Group H, R₁₅ and R₁₆ are H or --CH═CH--CH═CH--;

X is NH or O; and

Z represents a radical of the formula ##STR8## wherein m is 1 or 2, q is1 or 2, and r is 0 or 1.

The term "cycloalkyl" embraces cyclic radicals having three to about tenring carbon atoms, preferably three to about six carbon atoms, such ascyclopropyl and cyclobutyl. The terms "alkoxy" and "alkoxyalkyl" embracelinear or branched oxy-containing radicals each having alkyl portions ofone to about ten carbon atoms, such as methoxy group.

Specific examples of alkyl groups are methyl, ethyl, n-propyl,isopropyl, n-butyl, sec-butyl, iso-butyl, tertbutyl, n-pentyl,iso-pentyl, methyl-butyl, dimethylbutyl and neopentyl.

Included within the family of compounds of the described are thetautomeric forms of the described compounds, isomeric forms includingdiastereoisomers and individual enantiomers, and the-pharmaceutically-acceptable salts thereof. The term"pharmaceutically-acceptable salts" embraces salts commonly used to formalkali metal salts and to form addition salts of free acids or freebases. Since the compounds contain basic nitrogen atoms, such salts aretypically acid addition salts. The phrase "pharmaceutically-acceptablesalts" is intended to embrace alkyl quaternary ammonium salts andn-oxides. The nature of the salt is not critical, provided that it ispharmaceutically acceptable, and acids which may be employed to formsuch salts are, of course, well known to those skilled in this art.Examples of acids which may be employed to form pharmaceuticallyacceptable acid addition salts include such inorganic acids ashydrochloric acid, sulfuric acid and phosphoric acid, and such organicacids as maleic acid, succinic acid and citric acid. Otherpharmaceutically acceptable salts include salts with alkali metals oralkaline earth metals, such as sodium, potassium, calcium and magnesium,or with organic bases, such as dicyclohexylamine. All of these salts maybe prepared by conventional means by reacting, for example, theappropriate acid or base with the corresponding compound of theinvention.

The compounds that are the subject of the invention herein can beprepared according to the following reaction schemes. Z₁ is known and isprepared as described by Miyano and coworkers [J. Heterocyclic Chemistry(1987) 24, 47 for q=1; J. Pharmaceutical Sciences (1987), 76, 416 &references sited therein]. Z₂ is prepared according to schemes 1, 2, and3.

Scheme 1 describes the preparation of amino-azacycles Z₂. The BOC-amine1 (U.S. patent application Ser. No. 07/515,391) is deprotected withtrifluoroacetic acid and the resulting amine is cyclizedintramolecularly with the exocyclic olefin by treatment with iodine andpotassium iodide in the presence of sodium bicarbonate to yield thebridgehead iodide 2. Treatment of 2 with silver isocyanate affords thebridgehead isocyanate which may be hydrolyzed to give the requisiteamine Z₂ wherein r=0. Alternatively treatment of 2 with silver cyanideaffords the bridgehead nitrile which may be reduced to give the desiredaminomethyl-azacycle Z₂ wherein r=1.

Scheme 2 illustrates the preparation of Z₂ hydroxy azacycles. Hydrolysisof bridgehead iodide 2 affords the desired hydroxy azacycle Z_(2")wherein r=0. Alternatively treatment of 2 with silver cyanade followedby hydrolysis and reduction gives the desired hydroxymethyl azacycleZ_(2"') wherein r=1.

Scheme 3 illustrates the preparation of ethano-bridged azatricycles(Z_(2""), wherein m=2). The azabicycloketone 3 is converted first to itsO-benzyloxime. Removal of the N-BOC protecting group, followed byacylation with chloroacetic anhydride & iodide exchange, affords theintermediate 4. Cyclization under reductive radicalcyclizationconditions (Bu₃ SnH, AIBN) affords the ethano-bridged lactam 5.Reduction with lithium aluminum hydride affords the desiredethano-bridged azatricycle Z_(2""). ##STR9##

These examples, as well as all examples herein, are given by way ofillustration only and are not to be construed as limiting the invention,either in spirit or scope, as many modifications, both in materials andmethods, will be apparent from this disclosure to those skilled in theart. In these examples, temperatures are given in degrees Celsius (°C.)and quantities of materials in grams and milliliters unless otherwisenoted.

EXPERIMENTALS EXAMPLE A Preparation ofhexahydro-5-iodo-2,5β-methano-1H-3aα,6aα-cyclopenta[c]pyrrole ##STR10##Cis-N-t-butoxycarbonylhexahydro-5-methylenecyclopenta[c]pyrrole [SeeCo-pending application Ser. No. 07/515,391 filed Apr. 27, 1990] istreated with trifluoroacetic acid to afford an intermediatetrifluoroacetate ammonium salt, which is then treated with base and I₂to afford the title compound. EXAMPLE B Preparation oftetrahydro-2,5β-methano-1H-3aα,6aα-cyclopenta[c]pyrrol-5(3H)-amine##STR11## The iodo compound prepared in example A is treated with silverisocyanate to afford the intermediate N-formamide. This formamide ishydrolyzed to give the title compound. EXAMPLE C Preparation oftetrahydro-2,5β-methano-1H-3aα,6aα-cyclopenta[c]pyrrole-5(3H)-carbonitrile##STR12## The iodo compound prepared in example A is treated with silvercyanide in dimethylformamide to afford the title compound. EXAMPLE DPreparation oftetrahydro-2,5β-methano-1H-3aα,6aα-cyclopenta[c]pyrrole-5(3H)-methanamine##STR13## The nitrile compound prepared in example C is reduced withlithium aluminum hydride in etheral solvent to afford the titlecompound. EXAMPLE E Preparation oftetrahydro-2,5β-methano-1-3aα,6aα-cyclopenta[c]pyrrole-5(3H)-methanol##STR14## The nitrile compound prepared in example C is converted to theintermediate ethyl ester by treatment with aqueous ethanolic HCl. Theethyl ester is then treated with lithium aluminum hydride in etheralsolvent to afford the title compound. EXAMPLE F Preparation of1,1-dimethylethylhexahydro-5-[(phenylmethoxy)imino]cyclopenta[c]pyrrole-2(1)-carboxylate##STR15## Cis-N-Butoxycarbonylhexahydro-5-oxo-cyclopenta[c]pyrrole isreacted with O-benzylhydroxylamine hydrochloride and sodium acetate inmethanol to afford the title compound. EXAMPLE G Preparation ofoctahydro-2-(iodoacetyl)-5-[(phenylmethoxy)imino]cyclopenta[c]pyrrole##STR16## The title compound of example F is treated withtrifluoroacetic acid in methylene chloride at room temperature. Thevolatiles are removed under reduced pressure to afford a residue whichis treated with chloroacetic anhydride and triethylamine. Thechloroacetylated material is then reacted with NaI in acetone to givethe title compound. EXAMPLE H Preparation ofhexahydro-5-[(phenylmethoxy)amino]-2,5β-ethano-1H-3aα,6aα-cyclopenta[c]pyrrol-7-one##STR17## The title compound of example G is treated withtri-n-butylstannane in benzene at reflux containing a catalytic amountof AIBN. Upon workup the title compound is isolated. EXAMPLE JPreparation oftetrahydro-2,5β-ethano-1H-3aα,6aα-cyclopenta[c]pyrrol-5(3H)-amine##STR18## The title compound of example H is reacted with lithiumaluminum hydride in tetrahydrofuran to afford after workup the titlecompound. EXAMPLE 1 Preparation of6-chloro-N-(tetrahydro-1H-pyrrolizin-7a(5H-ylmethyl)imidazo[1,2-a]pyridine-8-carboxamide##STR19## 6-chloroimidazo[1,2-a]pyridine-8-carboxylic acid is reactedwith carbonyldiimidazole in dimethylformamide and subsequently with7a-aminomethylhexahydro-1H-pyrrolizine to afford the title compound uponworkup. EXAMPLE 2 Preparation of6-chloro-N-(tetrahydro-2,5β-methano-1H-3aα,6aα-cyclopenta[c]pyrrol-5(3H)-yl)imidazo[1,2-a]pyridine-8-carboxamide)##STR20## 6-Chloroimidazo[1,2-a]pyridine-8-carboxylic acid is reactedwith carbonyldiimidazole in dimethylformamide and subsequently withN-hexahydro-1H-2,5β-methano-3aα,6aα-cyclopenta[c]pyrrol-5β-amine toafford the title compound upon workup. EXAMPLE 3 Preparation of3-ethyl-N-(tetrahydro-1-pyrrolizin-7a(5H)-ylmethyl)indolizine-1-carboxamide##STR21## 3-Ethylindolizine-1-carboxylic acid is reacted withcarbonyldiimidazole in dimethylformamide and subsequently with7a-aminomoethylhexahydro-1H-pyrrolizine to afford the title compoundupon workup. EXAMPLE 4 Preparation of3-ethyl-N-(tetrahydro-2,5β-methano-1H-3aα,6aα-cyclopenta[c]pyrrol-5(3H)-yl)indolizine-1-carboxamide##STR22## 3-Ethylindolizine-1-carboxylic acid is reacted withcarbpnyldiimidazole in dimethylformamide and subsequently withN-hexahydro-1H-2,5β-methano-3aα,6aα-cyclopenta[c]pyrrol-5α-amine toafford the title compound upon workup. EXAMPLE 5 Preparation of3-ethyl-N-(tetrahydro-1-pyrrolizin-7a(5H)-ylmethyl)imidazo[1,2-a]pyridine-1-carboxamide##STR23## 3-Ethylimidazo[1,5-a]pyridine-1-carboxylic acid is reactedwith carbonyldiimidazole in dimethylformamide and subsequently with7a-aminomethylhexahydro-1H-pyrrolizine to afford the title compound uponworkup. EXAMPLE 6 Preparation of3-ethyl-N-(tetrahydro-2,5β-methano-1H-3aα,6aα-cyclopenta[c]pyrrol-5(3H)-yl)imidazo[1,5-a]pyridine-1-carboxamide##STR24## 3-Ethylimidazo[1,5-a]pyridine-l-carboxylic acid is reactedwith carbonyldiimidazole in dimethylformamide and subsequently withN-hexahydro-1H-2,5β-methano-3aα,6aα-cyclopenta[c]pyrrol-5α-amine toafford the title compound upon workup. EXAMPLE 7 Preparation ofN-(tetrahydro-1H-pyrrolizin-7a(5H)-ylmethyl)imidazo[1,2-a]pyridine-2-carboxamide##STR25## Imidazo[1,2-a]pyridine-2-carboxylic acid is reacted withcarbonyldiimidazole in dimethylformamide and subsequently with7a-aminomethylhexahydro-1-pyrrolizine to afford the title compound uponworkup. EXAMPLE 8 Preparation ofN-(tetrahydro-2,5β-methano-1H-3aα,6aα-cyclopenta[c]pyrrol-5(3H)-yl)imidazo[1,2-a]pyridine-2-carboxamide##STR26## Imidazo[1,2-a]pyridine-2-carboxylic acid is reacted withcarbonyldiimidazole in dimethylformamide and subsequently withN-hexahydro-1H-2,5β-methano-3aα,6aα-cyclopenta[c]pyrrol-5α-amine toafford the title compound upon workup.

The compounds of examples 1-8 find utility as antagonists of theserotonin 5-HT₃ receptor. As such they are useful for the treatment ofhumans and animals wherein antagonism of 5-HT₃ receptors is beneficial.Therapy is indicated for, but not limited to, the treatment of anxiety,psychoses, depression (especially depression accompanied by anxiety),cognitive disorders, substance abuse dependence and/or withdrawal,gastrointestinal motility disturbencies (including esophageal reflux,dyspepsia, irritable bowel syndrome), emesis caused by chemotherapeuticagents, and visceral pain. Additionally, the compounds of the presentinvention may find utility as enhancers of nasal absorption of bioactivecompounds.

The compounds herein exhibit 5-HT3 antagonism. 5-HT3 antagonism can bedetermined by the radioligand receptor binding assay as described hereinand in the in vivo Bezold-Jarisch reflex procedure.

Serotonin (5-HT₃) Procedure

GR65630 binds to the 5-HT₃ receptor. Brain cortices are obtained frommale rats and a membrane fraction prepared by standard techniques. 0.04mg of membrane prep is incubated with 0.2 nM [³ H]-GR656630 for 60minutes at 22° C. Non-specific binding is estimated in the presence of 1uM ICS 205-930. Membranes are filtered and washed 3 times and thefilters are counted to determine [3H]-GR65630 specifically bound.*

Results

Kd=2.46 nM

Bmax=154 fmol/mg protein

% Specific Binding: 70

    ______________________________________                                        Effect of Reference Compounds on                                              [H]-GR65630 Bound (0.2 nM)                                                    Compound    IC.sub.50  Ki       Hill Coefficient                              ______________________________________                                        Quipazine   0.5    nM      0.18 nM                                                                               0.86                                       ICS 205-930 2.2    nM      0.51 nM                                                                              1.0                                         5-HT        122    nM      0.39 uM                                                                              1.0                                         RU24969     320    nM      1.85 uM                                                                              1.0                                         Zacopride   0.55   nM      0.18 nM                                                                               0.86                                       ______________________________________                                    

*Literature Reference

Kilpatrick G. J., Jones B. J. and Tyers M. B. Identification anddistribution of 5-HT₃ receptors in rat brain using radioligand binding.Nature, 330: 746-748, 1987.

Bezold-Jarisch Reflex

The test sample is administered i.p. (mg/kg) to a group of 3 mice.Thirty minutes later, a 5-HT (0.25 mg/kg i.v.)-induced bradycardia isrecorded in pentobarbital anesthetized animals. A greater than 50percent (>50) reduction in the bradycardic response relative tovehicle-treated control mice is considered significant.

    ______________________________________                                                         Minimum Effective Dose                                       REFERENCE AGENTS:                                                                              (MED), mg/kg                                                 ______________________________________                                        BRL-43694        0.05                                                         cisapride        5                                                            cyproheptadine   5                                                            domperidone      >10                                                          GR-38032         0.5                                                          ketanserin       >10                                                          mecamylamine     2.5                                                          methysergide     >10                                                          metoclopramide   5                                                            scopolamine      2.5                                                          ______________________________________                                    

This method has been described by Saxena, P. R. and Lawang, A., Arch.Int. Pharmacodyn., 277:235-252, 1985.

Also embraced within this invention is a class of pharmaceuticalcompositions comprising one or more of the described compounds inassociation with one or more nontoxic, pharmaceutically acceptablecarriers and/or diluents and/or adjuvants (collectively referred toherein as "carrier" materials) and, if desired, other activeingredients. The compounds of the present invention may be administeredby any suitable route, preferably in the form of a pharmaceuticalcomposition adapted to such a route, and in a dose effective for thetreatment intended. Therapeutically effective doses of the compounds ofthe present invention required to prevent or arrest the progress of themedical condition are readily ascertained by one of ordinary skill inthe art. The compounds and composition may, for example, be administeredintravascularly, intraperitoneally, subcutaneously, intramuscularly ortopically.

For oral administration, the pharmaceutical composition may be in theform of, for example, a tablet, capsule, suspension or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit containing a particular amount of the active ingredient. Examplesof such dosage units are tablets or capsules. These may with advantagecontain an amount of active ingredient from about 1 to 250 mg,preferably from about 25 to 150 mg. A suitable daily dose for a mammalmay vary widely depending on the condition of the patient and otherfactors. However, a dose of from about 0.1 to 3000 mg/kg body weight,particularly from about 1 to 100 mg/kg body weight, may be appropriate.

For therapeutic purposes, the compounds of this invention are ordinarilycombined with one or more adjuvants appropriate to the indicated routeof administration. If administered per os, the compounds may be admixedwith lactose, sucrose, starch powder, cellulose esters of alkanoicacids, cellulose alkyl esters, talc, stearic acid, magnesium stearate,magnesium oxide, sodium and calcium salts of phosphoric and sulfuricacids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone,and/or polyvinyl alcohol, and then tableted or encapsulated forconvenient administration. Such capsules or tablets may contain acontrolled-release formulation as may be provided in a dispersion ofactive compound in hydroxypropylmethyl cellulose. Formulations forparenteral administration may be in the form of aqueous or non-aqueousisotonic sterile injection solutions or suspensions. These solutions andsuspensions may be prepared from sterile powders or granules having oneor more of the carriers or diluents mentioned for use in theformulations for oral administration. The compounds may be dissolved inwater, polyethylene glycol, propylene glycol, ethanol, corn oil,cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride,and/or various buffers. Other adjuvants and modes of administration arewell and widely known in the pharmaceutical art.

Although this invention has been described with respect to specificembodiments, the details of these embodiments are not to be construed aslimitations. Various equivalents, changes and modifications may be madewithout departing from the spirit and scope of this invention, and it isunderstood that such equivalent embodiments are part of this invention.

What is claimed is:
 1. A compound of the formula

    Ar--CO--X--Z

the stereoisomers and pharmaceutically acceptable salts thereof, wherein Ar represents a radical of the formula. ##STR27## Wherein in Group A, R₁ is hydrogen, or C₁₋₆ alkyl, R₂ is hydrogen, or halogen; In Group H, R₁₅ and R₁₆ are hydrogen or --CH═CH--CH═CH--; X is NH or O; and Z represents a radical of the formula ##STR28## wherein q is 1 or
 2. 2. A pharmaceutical composition for the treatment of anxiety, psychoses, depression, gastrointestinal motility disturbances or conditions responsive to 5-HT₃ antagonist effect comprising a therapeutically effective amount of a compound as defined in claim 1 and a pharmaceutically acceptable carrier or diluent. 